As giant cell tumors occurring in a bone and soft tissue, there are known osteoclastoma occurring in a bone (giant cell tumor of bone), giant cell tumor of tendon sheath occurring in a soft tissue, pigmented villonodular synovitis, and the like.
Osteoclastoma is a benign tumor frequently occurring in circumferences of the knee joints of young to middle- or advanced-aged persons, and the patients' man-and-woman ratio is 1:1.3 to 1.5, which means higher morbidity of women. Osteoclastoma accounts for about 5% of the total bone tumors, and accounts for about 20% of benign bone tumors. Although it is a benign tumor, the recurrence rate thereof is as high as 10 to 30%, and therapeutic treatment may sometimes be troubled by metastases to lung or malignant transformation. The major pathological finding is hyperplasia of multinucleated giant cells and monocyte cells, and spindle cells are observed among them. It is considered that the body of the tumor is not these multinucleated giant cells, but fibroblast-like spindle cells present in the stroma. Further, since it occurs in the vicinity of a joint such as knee joint, shoulder joint, and wrist joint, it is important how the recurrence is prevented, and how a treatment is performed with conserving the joint function.
Giant cell tumor of tendon sheath is a neoplastic disease occurring from tendon sheath, joint, or synovial membrane of synovial bursa. It is classified into the localized type and diffused type on the basis of the growth type of a lesion, and it is generally considered that a lesion of the localized type is synonymous to the giant cell tumor of tendon sheath, and giant cell tumor of tendon sheath of the diffused type is synonymous to the pigmented villonodular synovitis. Giant cell tumor of tendon sheath frequently occurs in women in their thirties to fifties, and in about 85% of patients, it occurs in the vicinity of joints of fingers or on the flexor tendon, and it secondly frequently occurs in toes. It may sometimes infiltrate into bones. As the major pathological findings, there are mainly orbicular-ovate to spindle-shaped histiocyte-like monocytes, and multinucleated giant cells and foam cells are accompanied by hemosiderosis. As the therapeutic treatment, tumor resection (simple enucleation) is performed as in the case of benign tumors, but the recurrence rate is reported to be 4 to 30%.
Pigmented villonodular synovitis occurs in relatively young adults not older than 40, and slightly more frequently occurs in women. It most frequently occurs in the knee joint, and also occurs in the hip, leg, elbow, shoulder joints, and the like. Villus images and tubercle-like proliferation of the synovial membrane are caused in the joints, and hemarthrosis is often observed. Since it may infiltrate into bones, secondary osteoarthritis may occur. As the pathological findings, there are intermingled synovial cell-like monocytes, multinucleated giant cells, foam cells, siderophores, inflammatory cells, and the like. As the therapeutic treatment, the tumor is surgically resected, but total resection is difficult, and therefore the recurrence rate is as high as 40 to 50%.
For all of osteoclastoma, giant cell tumor of tendon sheath, and pigmented villonodular synovitis, any effective therapies have not been developed at present, except for surgical operation.
Chondrosarcoma accounts for about 20% of primary malignant bone tumors, and shows the secondly highest occurrence frequency following that of bone sarcoma. It is histologically classified into conventional chondrosarcoma, periosteal chondrosarcoma, mesenchymal chondrosarcoma, dedifferentiated chondrosarcoma, clear-cell chondrosarcoma, extraskeletal myxoid chondrosarcoma, and the like. Typical chondrosarcoma frequently occurs in thirties to fifties, and slightly more frequently occurs in men. It most frequently occurs in the pelvic bone, and secondly frequently occurs in rib, proximal femur, proximal humerus, and distal femur. Mesenchymal chondrosarcoma frequently occurs in persons from between the age of ten and nineteen to those in thirties, who are younger than those favorite for conventional chondrosarcoma, and frequently occurs in jaw, spine, iliac bone, rib, distal part of femur, and the like. Dedifferentiated chondrosarcoma is a non-cartilaginous highly malignant tumor developed from a low malignancy conventional chondrosarcoma, and they are developed in contiguity with each other, but with a definite boundary. It occurs in persons in their fifties or sixties, and most frequently occurs in femur, and secondly frequently occurs in pelvis and humerus. Clear-cell chondrosarcoma frequently occurs in persons in their twenties to fifties, and in about ⅔ of the patients, it occurs in humeral head or femoral head. It also occurs in cranical bone, spine, and bones of hand and foot. Extraskeletal myxoid chondrosarcoma frequently occurs in persons in their forties and fifties, and may occur in deep part soft tissues of proximal parts of extremities such as thigh, and of the truncus, and soft tissues such as end parts of extremities, mediastinum and retroperitoneum. For these types of chondrosarcoma, any effective therapies have not been developed so far, except for surgical operation.
The peroxisome proliferator-activated receptor γ (PPARγ) is a protein belonging to the intranuclear receptor superfamily, and also functions as a transcription factor. Although PPARγ is mainly distributed over fat tissues, and participates in fat cell differentiation and the like, expression thereof is also observed in macrophages, vascular endothelial cells and the like. As the other activities thereof, it has been reported that the protein has an antidiabetic activity, anti-arteriosclerotic activity, bone metabolism related activity, antitumor activity, and anti-inflammatory activity. For example, it has been reported that activation of PPARγ induces apoptosis in various tumors (Non-patent documents 1 and 2), and expression of PPARγ has been confirmed in various cancer cells, such as cells of breast cancer (Non-patent document 3), colon cancer (Non-patent document 4), or lung cancer (Non-patent document 5). Moreover, it has been reported that activation of PPARγ is also induced by a non-steroidal anti-inflammatory agent besides a PPARγ ligand, resulting induction of cell death (Non-patent document 6).
However, neither expression of PPARγ in giant cell tumor occurring in a bone and soft tissue nor treatment targeting PPARγ have been reported so far. There has only been disclosed for an anti-inflammatory activity and suppression of cell proliferation of giant cell tumor of tendon sheath and pigmented villonodular synovitis which is a disease analogous to osteoclastoma, by suppression of IL-6 production (Patent document 1).